Monocyte/macrophages (M/Mphi) play a key role in the neuropathogenesis of HIV-associated dementia (HAD) through inflammatory responses that cause neuronal injury and apoptosis. Prior to the advent of highly active anti-retroviral therapies (HAART), HAD was an acute neurodegenerative disease that was aggressive and terminal. Fortunately, where treatment with HAART is available, there has been a decrease in the incidence and severity of HAD. However, no data is available to indicate that HAART protects the brain or reverses the neuropathology associated with HIV infection. In fact, studies from our laboratory suggest that HAD-associated peripheral markers and M/Mqb-derived factors are diminished but still present. It is possible that HAD has become a chronic neurodegenerative disease. It is the overall hypothesis of this proposal that HAD may manifest a peripheral profile years before clinical dementia. Our Specific Aims are: 1) To develop a M/Mphi expression profile from individuals with HAD using cDNA microarrays and proteomics technology and 2) To identify unique proteins secreted from M/Mphi supernatants of patients with HAD using proteomics technology. To identify signaling pathways and structural/functional protein changes associated with supernatant-treated human brain aggregates using cDNA microarrays and proteomics. To determine whether or not APOE genotype affects these neural cell changes. Since neurodegeneration related to HAD may occur years before becoming clinically evident, it is important to identify individuals early in the disease process to improve the response to therapeutic intervention. Results from these studies will not only profile individuals at risk for dementia but also better elucidate the mechanisms for the risk.